Manipulating normal estrogen physiology as a therapeutic approach in cancer

背景：生殖系统的癌症本质上是以性二型的方式发生的 并受到生殖激素和性激素反应失调的影响。这个 雌激素在大多数乳腺癌病理生物学中的作用及内分泌的积极作用 对于这种疾病的治疗结果已经很好地确定了。然而，这种疾病的发生率和长期结果 患有各种非生殖性癌症的患者也表现出性别二型性(例如肺癌， 黑色素瘤、胶质母细胞瘤和甲状腺癌)。鉴于这些差异背后的机制是 已确定的复杂和多因素的促成因素是吸烟、日晒、 饮酒、饮食和职业环境。性的贡献被低估了 荷尔蒙本身与非生殖性癌症的病理生物学有关。我们已经确定癌细胞 雌激素/雌激素受体-α(ERA)在免疫系统和大脑中的外在作用 在几种不同癌症的动物模型中的肿瘤病理学。雌激素促进卵巢癌的发生 免疫抑制肿瘤微环境通过直接作用于髓系细胞而导致衰减 T细胞活化/功能的变化。然而，抑制大脑中特定部位的ER活动具有矛盾的效果 增加来自不同来源组织的肿瘤的生长。了解癌细胞的外源性 ER的药理学将告诉我们如何最好地使用现有的内分泌治疗方法，对于 开发下一代调节剂并支持开发新的药物组合 乳腺癌和妇科癌症以及其他起源于生殖系统以外的癌症的治疗。 假设：ER调节剂对不同癌症的最大治疗效果将通过 对雌激素对癌细胞内在作用的有力抑制的干预措施的发展，展示 对肿瘤免疫细胞谱系/功能有有利作用，不干扰体内平衡反馈 大脑中调节影响肿瘤生物学过程的表达的机制。 目的：(1)明确肿瘤相关髓系细胞ER影响肿瘤病理生物学的机制。 (2)明确ER在大脑中表达调节影响生长的过程的机制(S) 肿瘤的症状。(3)评价选择性靶向肿瘤细胞外源性ER活性的治疗方法。 影响：内分泌疗法对乳腺癌和其他雌激素调节的癌症的有效性 由于专注于开发针对癌细胞内源性雌激素/雌激素作用的药物，这一研究受到了限制。通过 明确内质网调节免疫细胞功能的机制，以及它如何调节下丘脑 影响外围肿瘤生物学的活动将有可能开发下一代ER调节剂 针对有利的癌细胞内在和外在作用进行了优化。这样的疗法应该对 ER阳性和阴性(生殖性和非生殖性)癌症的治疗。

Background: Cancers of the reproductive system, by their very nature, occur in a sexually dimorphic manner and are influenced by exposure to reproductive hormones and dysregulated responses to sex steroids. The contributions of estrogens to the pathobiology of most breast cancers and the positive impact of endocrine therapies on outcome in this disease are well established. However, the incidence and long-term outcomes of patients with a variety of non-reproductive cancers also demonstrate sexual dimorphism (e.g. lung cancer, melanoma, glioblastoma and thyroid cancer). Whereas the mechanisms underlying these differences are complex and multifactorial, established contributing factors are gender differences in smoking, sun exposure, alcohol consumption, diet and occupational environments. Underappreciated are the contributions of sex hormones themselves to the pathobiology of non-reproductive cancers. We have determined that cancer cell extrinsic actions of estrogens/estrogen receptor-alpha (ERa) in the immune system and in the brain contribute to tumor pathology in animal models of several different cancers. Estrogens facilitate the development of an immune suppressive tumor microenvironment through direct actions on myeloid cells resulting in the attenuation of T cell activation/function. Inhibition of ER action in specific loci in the brain, however, has the paradoxical effect of increasing the growth of tumors from different tissues of origin. Understanding the cancer cell extrinsic pharmacology of ER will inform how best to use existing endocrine therapies, be instructive as to approaches to develop the next generation of modulators and enable the development of new drug combinations for the treatment of breast and gynecological cancers and other cancers originating outside of the reproductive system. Hypothesis: Maximal therapeutic efficacy of ER modulators for different cancers will be realized with the development of interventions that achieve robust inhibition of cancer cell intrinsic actions of estrogens, exhibit favorable effects on immune cell repertoire/function in tumors, and do not interfere with the homeostatic feedback mechanisms in the brain that modulate the expression of processes that impact tumor biology. Aims: (1) Define the mechanisms by which ER in tumor associated myeloid cells impacts tumor pathobiology. (2) Define the mechanism(s) by which ER expression in the brain regulates processes which impact the growth of tumors. (3) Evaluate therapeutic approaches to selectively target tumor cell extrinsic activities of ER. Impact: The effectiveness of endocrine therapies for breast cancer and other estrogen-modulated cancers has been limited by the focus on developing agents that target cancer cell intrinsic actions of ER/estrogens. By defining the mechanisms by which ER regulates immune cell function, and how it regulates hypothalamic activities that impact tumor biology in the periphery it will be possible to develop next generation ER modulators optimized for favorable cancer cell intrinsic and extrinsic actions. Such therapeutics should have utility for the treatment of ER-positive and -negative (reproductive and non-reproductive) cancers.